Case Studies

Here at Geneuity, we do a lot of contract research work for sponsors of clinical trials. That sometimes means developing and validating custom assays that aren’t available off the shelf. And this, in turn, often means developing special interfaces for data capture that can’t be configured inside OpenClinica (as yet).

Does that mean we jettison OpenClinica?

No, absolutely not!

Since OpenClinica is open source and dedicated to interoperability, it can be easily extended. This article describes the specifics of one such case involving XForms.

A while back, Geneuity was developing an ELISA to measure the abundance of a specific protein in plasma. We needed a single web form with a spreadsheet-like feel and functionality in which lab technicians could enter data, interpolate unknowns, send the resulting interpolated values for insertion into OpenClinica and then perform source data verification. Additionally, the form needed to be pre-populated with the accession numbers of specimens requiring testing. The form had to work on any browser and not be dependent on any browser plugins. And we had to have it fast.

Impossible? No, not with XForms and the open source XForms renderer betterFORM.

XForms have several advantages. First of all, you author the forms in relatively simple XML while the complicated AJAX that makes the spreadsheet-like feel and functionality is rendered by the renderer and presented to the client browser for you. Secondly, XForms allows you to easily call upon webservices to populate data items in the form. In our case, we developed three such services: one to return a list of accession numbers corresponding to specimens yet to be tested along with corresponding hyperlinks directed inside OpenClinica for rapid source data verification (SDV); another to calculate and graph a standard curve and to interpolate the specimen unknowns; and still another to insert the interpolated values into OpenClinica. The data flow is diagrammed in Figure 1. Although a great deal is going on behind the scenes, the user experience is seamless as a single form is being used while data retrieval and refreshment are being done without interrupting the display (thanks to AJAX as automatically implemented by betterFORM). The form itself is pictured in Figure 2.

And there you have it. The bottom-line: no matter how complicated your data capture requirements are, you can count of the interoperability of OpenClinica.

Figure 1. First, the lab tech initially summons the XForm which calls upon OpenClinica via a webservice for the list of specimens for which there are no test results. The tech enters the data and clicks on the appropriate button to call for data interpolation and calculation. After review of the results, the tech then submits the data for insertion into OpenClinica (for more on this see here). Finally, the tech performs source data verification using the hyperlinks populated in the XForm as the result of step 1. Figure 2. This is a snapshot of the XForm as it exists after interpolation and calculation. Only two specimens are shown, but usually there are many more in a batch.

At Geneuity Clinical Research Services, we do lab tests for trial sponsors. As readers of this blog know, we use OpenClinica internally as an LIS (laboratory information system), but as more and more drug companies and CRO’s adopt OpenClinica we foresee the day when we will be using their installations as our LIS, not ours. A common platform will eliminate lots of duplicated effort and will allow for real-time transparency and better collaboration. But it will also require sponsors to design their CRF’s with their contracting laboratories in mind. In this article, we describe how this could be done.

First, consider specimen collection and tracking. Normally, trial sponsors don’t consider doing this within the context of OpenClinica. But they should. Let’s say a specimen accidentally thaws in transit between the collection site and the contract lab. Shouldn’t that fact be summarily recorded in the same context as the resulting lab test whose value may ultimately be reported to the FDA? I should say so.

So, can OpenClinica be configured to do this? Yes and easily. A separate CRF dedicated to specimen collection could be designed and assigned to each event. Alternatively, a specimen section could be added to already existing CRF’s. Either way, fields for such things like accession number and specimen type could then be included. These would be filled in by site personnel responsible for specimen collection. Additional fields like ‘shipping deviations’ and ‘laboratory receipt date’ could also be included and would be filled in by lab personnel upon specimen delivery to the testing lab. When it comes time for data analysis, the sponsor can use OpenClinica’s data export capabilities to exclude or include those lab results with shipping deviations and to investigate the consequences.

Other important aspects of specimen collection include printing labels to barcode samples and generating an attendant paper manifest (know as a requisition) against which labs can check incoming shipments of specimens. OpenClinica can’t do such things currently. It would require a whole new software module, but lots of added value could be achieved if one were written. For instance, one can envision that after accessioning a specimen, site personnel could print a corresponding requisition from the same application window. Also, imagine the time savings if lab personnel could conveniently print barcode labels after receiving a specimen and recording its receipt date and shipping deviations (if any). And because the paper requisitions would be generated within the context of OpenClinica, subsequent source data verification by lab personnel could be expedited using QR-encoded URL’s that drill-down into the patient-event matrix. For more on this, see here.

Specimen tracking is just part of the story when it comes to sponsors and their contract labs. Getting lab data from the laboratory testing platform into OpenClinica is another. Recently during OpenClinica’s March 22 Global Conference in Bethesda, Akaza Research and Geneuity did a live demonstration of how this can be achieved using a set of MirthConnect channels. A batch of raw lab data keyed only to accession numbers was sent from Geneuity’s corporate headquarters in Maryville, TN to a remote OpenClinica installation hosted at Akaza’s Waltham, MA facility where it was inserted into the database programmatically via an awaiting web service. The insertion was streamlined, secure and seamless. When setting up a trial, sponsors should think about the lessons this demo provides and consider distributing already configured and validated MirthConnect channels to their contract labs. In this way, sponsors can control how their data is treated and understand every detail of its electronic provenance. And because MirthConnect can be configured to store its history, the trial’s audit trail can be extended upstream to the data’s very source.
Finally, consider invoicing. Contract labs have to be paid when they do a test. Monthly invoicing reports could be generated from OpenClinica by configuring an appropriate ‘data set’ and having it execute at the end of each month using the application’s new built-in quartz scheduler. In this way, billing would be a snap and everybody would be on the same page.

In summary, how can trial sponsors configure OpenClinica to collaborate better with their contract labs? Do the following, keeping the workflow shown in Figure 1 in mind:

1. Include a specimen accessioning CRF for each event. Educate your collection-site people and your lab people as to who is responsible for which fields. Use OpenClinica’s internal messaging system to remind people of their roles when the study is actually underway.
2. Exploit OpenClinica’s web services framework to enable batch uploads of laboratory data.
3. Configure and validate MirthConnect channels to get the lab results from the source data files to your OpenClinica installation.
4. Distribute these channels to your lab contractors and educate them on their use.
5. Configure OpenClinica to automatically generate monthly data sets for billing purposes.

The bottom-line: OpenClinica is infinitely configurable and sponsors should start doing so with their lab contractors in mind. The result will mean both better collaboration and lower costs.

Figure 1: A specimen is collected from a subject on site. The on-site data manager logs into OpenClinica and accessions the sample and prints an accompanying hard-copy requisition. The sample is then shipped to the contracting laboratory where lab personnel log into OpenClinica and indicate they have received the sample. Specimens are then tested in batch and the results are then uploaded en masse into the sponsor's installation of OpenClinica using a thoroughly vetted, validated and auditable MirthConnect channeling system.

The developers of OpenClinica like to say they are ‘powering the electronic data capture (EDC) revolution’ in clinical data management and indeed that’s the case. However, sometimes there’s no substitute for paper, especially when it comes to tracking and handling laboratory specimens. We at Geneuity should know: testing lab specimens for clinical trials is our business. This article shows how OpenClinica and paper records can augment one another through the use of URL-encoding barcodes.

Readers of this blog probably already know the drill: a specimen is collected, a paper requisition is attached and the whole kit and kaboodle is mailed to a laboratory for testing. When a specimen arrives at Geneuity, we log into OpenClinica’s web interface, look up the patient and event pairing in the subject matrix as specified by the requisition and then finally type in the values for items like accession number, receipt date, shipping deviations, freezer location and the like. When one or two specimens arrive, this process (called ‘accessioning’) is no problem; when 20 to 60 arrive, it rapidly becomes tedious.

In a more perfect world, things would be easier and more automated. Here’s one potential scenario to help achieve this. In addition to all the necessary information in human-readable form, also print on the requisition a QR barcode that encodes the URL corresponding to the appropriate event case report form (CRF) in the study’s OpenClinica installation. For instance, consider the example shown in Figure 1.

It encodes: “https://myOpenClinicaInstall.com/InitialDataEntry?eventCRFId=1” (for illustration only, not intended to link anywhere for real). Upon being scanned with an appropriate hand-held reader (or smart-phone even), this would automatically direct the lab technician’s browser to the correct screen to input the attendant accessioning information for study event number one. This would eliminate the manual look-up step described above and would reduce tedium and errors as a consequence.

Implementing this idea would require enabling OpenClinica to print out requisitions. While challenging, this would not be impossible. Indeed, middle-ware like MirthConnect may make it relatively easy.

Here’s another example of paper and OpenClinica working together, one that Geneuity actually implements currently to facilitate quality control. Prior to testing a batch of specimens, lab technicians here use a custom Mirth channel to print out details of the samples to be tested. A dummy example is shown in Figure 2. As shown, it includes a simple linear barcode of the accession number, the principle means of tracking specimens in a clinical lab. Scanning this saves the technician from having to type it into the testing platform during set-up. It also contains a QR barcode specifying the event-specific URL that directs the technician where to go to review the data upon automatic upload into OpenClinica. Having this URL handy means the technician doesn’t have to look it up in the subject matrix table which oftentimes has hundreds or even thousands of entries.

URL-encoding barcodes are a cheap and reliable way of linking physical objects with on-line databases, and nowhere is this link more critical than when tracking clinical specimens. Thanks to Akaza’s commitment to open source, it’s easy to incorporate this technology into OpenClinica and to realize the myriad of benefits.

Figure 2: A list of specimens to be tested reported by a Mirth channel extracting from a mock OpenClinica installation. The linear barcode helps with data entry at the testing platform while the 2D QR barcode is used to direct the lab tech's browser to the appropriate URL in OpenClinica for subsequent data review after testing is complete.

As mentioned previously, we at Geneuity Clinical Research Services are big fans of OpenClinica and are even more so now with the upcoming release of version 3.0 with its new web services capability. This article describes how we exploit this new feature to help automate entry of lab results, a particularly important topic given that we do lots of batch testing of specimens and oftentimes test the same specimen for many different analytes.

Prior to 3.0, you had three options when it came to CRF data entry. The first was to log into OpenClinica’s web interface and manually enter your data. This was no problem so long as you didn’t have lots and lots of data. But we did.

Alternatively, you could upload a flat file of your data as long as it was formatted in XML and associated with the appropriate subject id’s and visit descriptions. Assembling this file wasn’t trivial though and manually looking up each specimen’s subject and event nearly defeated the purpose of the procedure, which was to save time and effort.

Finally, you could do what we did: write custom code to automate the job. Lab data is amenable to this sort of approach because it is always tagged with something called an accession number that uniquely identifies it. When designing CRF’s, we always make sure to include a field for the event’s accession number, and when a specimen first arrives through our door the first thing we do is to log into OpenClinica and enter the specimen’s accession number in the appropriate event’s CRF. Because the number is unique to the study, this entry effectively tags the event and provides a ‘hook’ inside the database so that the event_crf_id of any data item subsequently annotated with the accession number can be easily looked up using a database query like so: ‘SELECT event_crf_id FROM item_data WHERE value = ‘<accession_number>’. This, in turn, gives you the requisite information to insert the lab data thusly: ‘INSERT INTO item_data VALUES (‘event_crf_id’, ‘value’ …’ provided you also know the item_id.

To implement this strategy, we wrote custom servlets that operated within the context of our OpenClinica installations. More recently, we configured MirthConnect channels to do the same. They worked well and data entry was greatly expedited, but the coding was complex and had to be refactored over and over again for each study and for every CRF change. While helpful, this strategy wasn’t sustainable in the long run.

Luckily, the latest version of OpenClinica provides a way out. It incorporates the Spring WS Framework which allows programmers to write something called a ‘web service.’ A web service digests and acts upon XML data sent to it on an on-demand basis over a network. The source need not be a human being uploading data on a web form, but, more usefully, it can be, say, a clinical testing platform automatically spitting out HL7 messages. This, of course, is ideal in our case. So we wrote a web service called ‘EventDataInsert’ that parses XML containing lab data values annotated with accession numbers and item names, looks up the corresponding event_crf_id’s and item_id’s, and inserts the data into item_data accordingly. The service is generic enough so that it doesn’t have to be refactored for each and every study, but it does make some critical assumptions. Namely, it assumes that both accession numbers and item names are unique. So care has to be taken to ensure both these preconditions are met.

The power of EventDataInsert doesn’t just lie in the fact that it handles inserts on an unattended basis, but also in that, like most web services, it requires only simple XML as input. The latter makes the source of the data irrelevant as long as it can be correctly mapped and transformed into XML. We often use MirthConnect to do this, using it’s easy-to-use graphical interface to configure channels between incoming raw data and OpenClinica’s web-service interfaces.

The figure below shows a typical deployment of OpenClinica at Geneuity. MirthConnect is used not only to get data into OpenClinica but also to generate canned PDF reports of the results. This scenario works for us and gets easier and easier to maintain as OpenClinica evolves new electronic data capture features and makes old ones ever more robust.

Here at Geneuity Research Services, we do laboratory tests for clients
conducting clinical trials. We are a one-­stop shop, handling everything
from routine clinical assays to esoteric molecular analyses. We use
OpenClinica as an in-­house LIS to keep track of work­flow and to help
with administrative tasks like billing and specimen archiving. This isn’t
exactly what the developers of OpenClinica had in mind originally. The
application was designed from the point of view of trial sponsors, not their
subcontractors. But it works very well for us nonetheless. In this article,
we briefly describe how we do it.

As everybody who uses OpenClinica knows, defining your event x
CRF matrix is the most important step in configuring a trial. When a
client comes to us with a new trial, we do just that. We are careful
to reproduce the anticipated flow of events and patient groupings
just as designated by the trial’s specifications. “Why bother?”
you’re probably asking. “You’re just a subcontractor. That’s not your
concern.” But it is. Invariably, specimens get mislabeled and
inappropriate tests get ordered, and we’re able to detect many such
mistakes by doing a quick visual inspection of OpenClinica’s patient
x event dashboard with its easy-­to-­take-­in iconification. We feel
that this double-checking is part of our service to the sponsor.

CRF design is our next consideration. In this case, we don’t
try to reproduce everything required from the sponsor’s point of
view. Instead, we design a set of CRF’s that reflects just our role
as a contract clinical laboratory. This means that our CRF’s are far
more narrowly focused and less complicated. But it also means we
include some unique types of fields for pricing, specimen archiving
and the like, items that a trial sponsor usually doesn’t need to
address in their CRF’s but which are very helpful to us.

We are very careful how we name our items when crafting our
CRF’s. Specifically, we use the same terminology across our trials
whenever possible. For instance, the field for a specimen’s accession
number is always named ‘accession_number‘. Likewise, we consistently
use the names ‘freezer‘, ‘received_date‘, ‘price‘, ‘shipping_deviation‘
and ‘%assay_date‘ (where % is the wildcard string).

Using such a controlled vocabulary is vital in our case because
we use a separate installation of OpenClinica for each study and
employ the postgresql contrib module ‘dblink’ to federate their
attendant databases for querying. A helter­skeleter vocabulary would
render the latter problematic, to say the very least.

For example, we wrote a federated database procedure we callaccessions(). When executed, it consults the accession_number field
in all our installations and returns the number of accessioned
specimens broken down by trial name. This table lists some of the
federated procedures we’ve developed and their functionality.
Collectively, they provide us with a real­time, global snap­shot of
our work­flow and freezer contents.

Because OpenClinica is web­-based and has finely grained user
roles, our clients can remotely log into their respective
installations at our site with read­-only privileges and see the
status of their specimens whenever they want. Conversely, when we
think a specimen has been mislabeled or have some other issue, we can
call a client and direct them to a particular URL displaying the
pertinent information and seek clarification. OpenClinica thus
becomes a shareable laboratory notebook between us and our clients.

The bottom­line: OpenClinica works for Geneuity. Because
OpenClinica is open source, elegantly designed and well documented,
we are able to tailor the application to our needs. In the spirit of
mutual collaboration and aid fostered by OpenClinica’s lead
developers at Akaza Research, we’re making our federated procedures
freely available. They can be downloaded here.

The use of electronic data capture (EDC) systems in health care, and especially in clinical trials, has been the object of significant research given the potential advantages like improved data quality, reduced cost, and increased trial repeatability. Despite significant interest and promised benefits, real adoption has been somewhat limited to date with most successful implementations performed in the field of pharmaceutical clinical trials. This can be attributed in part to the lack of underlying consistent and reusable internal data models and the high cost and complexity in customizing most EDC systems.

A potential alternative to traditional EDC software is the use of Open Source Software (OSS), broadly defined as software that is distributed as a freely available and freely modifiable system. This freedom gives the user the opportunity to perform structural modifications and adaptations to better integrate the software with pre-existing IT infrastructures, or to adapt it to local needs and requirements. There are many examples of large scale open source software (OSS) systems in health care, including the VISTA electronic health record system, used in the US Department of Defense and in several hundred installations across the world, the Care2X system, Indivo health, and the OpenClinica EDC system. The use of open source software facilitates the harmonization of a coherent and comprehensive data model that can be reused across different systems. In our work, ICF (the WHO classification for functioning and disability) has been selected as the underlying representational model, and implemented in the OpenClinica EDC software. The experimentation involved more than 10 Italian regions, with multiple hospitals and care centers. The EDC system was designed to test the effectiveness of ICF as a basis for data collection on disability and functioning in a wide spectrum of pathologies.

The complete WHO-ICF classification was imported from the CLAmL XML representation into the LexGrid editor, a tool created by Mayo Clinic for the purpose of editing and maintaining ontologies and classifications. Starting from this intermediate representation, the classification was first translated into the Italian language and then exported back into the CLAmL representation; this form was also used as the basis for the creation of the internal EDC data model, later imported into the OpenClinica platform. From this visual representation, a group of experts designed the set of forms that comprise the web application; later, the database structure and the final application templates were fixed and published on a public web site. The joint use of ICF as a representational model for an Electronic Data Capture system, coupled with the choice of open source software, yielded a significant reduction in the cost and implementation time of a multiregional EDC system. The ease of use of the web interface also facilitated interactions with medical experts to quickly implement alternative data representations and to create a stable and fast platform that is currently being used in an actual trial. OpenClinica demonstrates that open source is stable and ready to be used even in the strictest clinical trials, and that by using open source it is possible to create clinical research applications in a faster and more cost effective way.

A recent issue of Applied Clinical Trials Online features a case study of OpenClinica Electronic Data Capture (EDC) adoption by German device company, Retina Implant, AG. Here’s a short excerpt:

“Last summer, Retina Implant started using OpenClinica for its latest trial, which is comprised of 11 studies. Currently, five of those studies have acquired subjects and are up and running with the OpenClinica CRF process. Randomization of study subjects are done outside OpenClinica, as it doesn’t have this feature. So far, Hekmat is appreciative of the flexibility of the platform, its ease of use among the global site staff, and the ability to view data in real-time via the Web browser.”